S-1 is an oral chemotherapeutic drug obtained by blending three ingredients, i.e., tegafur, gimeracil, and oteracil potassium, which is generally and widely used as neoadjuvant chemotherapy in head and neck squamous cell carcinoma, gastrointestinal cancer, and other types of cancers. Among the ingredients, tegafur is a prodrug of 5-fluorouracil (hereinafter abbreviated as 5-FU), and inhibits DNA biosynthesis, thereby exhibiting an anticancer action. Gimeracil selectively inhibits a metabolizing enzyme of 5-FU to increase a 5-FU concentration, thereby augmenting an antitumor effect. Further, oteracil potassium is distributed mainly in a gastrointestinal tissue and shows an action of alleviating gastrointestinal tissue impairment.
The present inventors reported that a tumor reduction effect was found in 61.2% of patients who received neoadjuvant chemotherapy with S-1 monochemotherapy (“Journal of Cancer Science and Therapy,” 2010, 2(5), p. 132-135). However, administration effects of S-1 vary depending on patients. Therefore, in some cases, patients with no clinical effect suffer from side effects and have poor prognosis.
In cancer chemotherapy, it is known in general that incidence of side effects due to a chemotherapeutic drug is observed in many patients, and that some patients do not show any response to the chemotherapeutic drug. Therefore, there often occurs such a situation that even though many patients suffer from serious side effects, no therapeutic effect can be obtained, resulting in cancer progression and poor prognosis. Presence of resistance to the cancer chemotherapy is well known at the present time. For the purpose of reversing chemotherapeutic drug resistance, various researches have been made on a mechanism thereof and a drug for augmenting an effect of chemotherapy (e.g., “Cancer Research,” 2004, 64 (22), p. 8167-8176, “Experimental Cell Research,” 2003, 288 (2), p. 403-414, “International Journal of Oncology,” 2003, 22(5), p. 945-953, “Biochimica et Biophysica Acta,” 2002, 1587(2-3), p. 194-205, and “Anticancer Research,” 2008, 28, p. 9-14 and Japanese Patent Application Laid-open No. 2009-242378 and Japanese Patent Application Laid-open No. 2011-102255).
For the purpose of selecting a chemotherapeutic drug suitable for a patient to be subjected to chemotherapy, a method of determining a therapeutic effect of a chemotherapeutic drug is carried out in some cases prior to its administration. For example, in advanced medical therapy, a method comprising using a cell culture technology has been carried out as means for collecting a cancer tissue from a cancer patient and assessing whether cancer cells contained in the cancer tissue are resistant or sensitive to a chemotherapeutic drug. Specifically, there has been carried out a method comprising: collecting a cancer tissue from a cancer patient; separating cancer cells from the cancer tissue; culturing the cancer cells using a cell culture technology; adding a chemotherapeutic drug, i.e., an anticancer drug prepared at each concentration to a culture solution of the cancer cells at the stage in which the cancer cells grow to some extent; and measuring whether the cancer cells are sensitive or resistant to the anticancer drug based on growth of the cancer cells. However, a diagnosis method comprising such a technique for culturing cancer cells as described above is rarely utilized as a diagnosis method in a clinical field because it takes 3 to 4 days to obtain diagnosis results and the technique for cell culture is complicated.
In view of the foregoing, an attempt has been made to develop a method of determining quickly a therapeutic effect of a chemotherapeutic drug prior to its administration. The inventors of the present application also disclosed methods of determining a therapeutic effect of cisplatin based on gene expression (International Patent WO2008/047947A and Japanese Patent Application Laid-open No. 2009-247309). Specifically, the inventors disclosed, as the methods of determining a therapeutic effect of cisplatin, a method comprising: measuring expression level of at least one gene selected from a phosphodiesterase 3B gene, a platelet derived growth factor C gene, a polycystic kidney disease-2 gene, a neuregulin 1 gene, and a lumican gene; and carrying out determination based on the expression level; and a method comprising: measuring expression level of at least one gene among 195 kinds of genes such as a decorin gene in addition to the above-mentioned genes; and carrying out determination based on the expression level.
Decorin (hereinafter sometimes abbreviated as DCN) is a small proteoglycan that is produced by fibroblasts. A proteoglycan is a protein having one or more glycosaminoglycan chains. A core protein of decorin has a molecular weight of about 40,000 Da, and its sequence has already been determined.
DCN is known to be an extracellular matrix protein and regulate cell-cell adhesion and cell movement through collagen fibril formation and stabilization, thereby participating in wound healing and inflammatory responses. Further, it has been reported that DCN binds to an epidermal growth factor receptor (hereinafter abbreviated as EGFR) on a cell membrane, thereby participating in various functions such as cell growth and apoptosis via a mitogen-activated protein kinase (hereinafter abbreviated as MAPK) pathway and a phosphatidylinositol 3-kinase/AKT (hereinafter abbreviated as PI3K/AKT) pathway (see FIG. 1 and “The Journal of Biological Chemistry,” 2011, 286, p. 34712-34721, “NEOPLASIA,” 2009, 11(10), p. 1042-1053, and “The International Journal of Biochemistry and Cell Biology,” 2008, 40, p. 2120-2128).
Hitherto, in order to determine a therapeutic effect of chemotherapy with S-1 prior to its administration, there has been used a method comprising: culturing cancer cells collected from a cancer tissue of a cancer patient in the presence of S-1; and determining responsiveness of the cancer cells to S-1 based on growth of the cancer cells. However, such determination method requires much time and involves a complicated cell culture technique, resulting in a low utility value for many patients as a diagnosis method in a clinical field. Hence, the method is rarely utilized in a clinical field and has not yet been put into practical use.